Process for the preparation of 17, 20-hydroxyketones of the pregnane series and new and useful compounds of the said series



,hydroxyketones of the recited type.

Patented Feb. 9, 1 954 PROCESS FOR THE PREPARATION OF 17,20-

HYDROXYKETONES OF THE PREGNANE SERIES AND NEW AND USEFUL COM- POUNDS OF THE SAID SERIES Karl Miescher, Riehen, and Julius Schmidlin,

Basel, Switzerland, assignors toCiba Pharmaceutieal Products, Inc., Summit, N. J.

No Drawing. Application February 5, 1951,

Serial No. 209,516

Claims priority, application Switzerland February 10, 1950 8 Claims.

The present invention is concerned with the preparation of saturated and unsaturated 17,20- hydroxy-ketones of the pregnane series containing a free, esterified or etherified hydroxy group in the 21-position, and with certain new compounds of the said series.

Such hydroxy-ketones of the pregnane series are of very great importance. Thus, for example, cortisone-the A -3,11,20-triketo-l'la-dihydroxypregnene--and substance S-the A -3,20-diketo- 1711,21 dihydroxy-pregene-are 17,20-hydroxyketones. Various processes for the preparation of these compounds are known. Thus, for example, they may be prepared by treating the corresponding A 21 acetoxy pregnene compounds with hydroxylating agents, such as osmium tetroxide, followed by partial oxidation of the obtained 17,20,21-triols. However, this process requires at least 3 stages for the preparation of the desired 17,20-hydroxy-ketones. Moreover, the yieldsparticularly in the last stepare very unsatisfactory.

A primary object of the present invention is the embodiment of a process for the preparation of the said 17,20-hydroxyketones, which is free of the disadvantages of the prior art processes. A further object is the preparation of new 17,20- These objects are realized by the present invention, according to which the desired 17,20-hydroxyketones are directly obtained by subjecting a pregnene compound containing the grouping in the l7-position-X standing for a free, esterified or etherified hydroxy group-to the action essesand, moreover, only one reaction stage is required.

The starting materials are preferably esterified or etherified 2l-hydroxy-pregnene compounds, for example those which contain in 21- position an acyloxy group, such, for instance as acetoxy, pr pion-yloxy, succinyloxy, benzoyloxy, tosyloxy, etc. or a halogen'atom, or an alkoxy group, such for instance as methoxy, ethoxy, etc,

or a hydroxy group etherified with a sugar radical, such as the radical of d-glucose, galactose,

position.

maltose, lactose, etc. The starting materials may additionally be substituted in the 5-, 6-, 7-, 12- and, more particularly, in the 3- and ll-positions, for example by free or functionally converted 0x0 or hydroxy groups, as for instance by acyloxy groups, such as acetoxy, propionyloxy, benzoyloxy, tosyloxy, etc. groups or halogen atoms, by alkoxy groups such as methoxy or ethoxy groups, etc, or by epoxy groups, for example in the 3,9-

Moreover, they may also contain a double bond in the 3-, 4-, 5-, 9- and/or 11- position. If necessary, any such double bond may be intermediarily protected in known manher, for instance by saturation with halogen or hydrogen halide or by conversion into pentacyclic isosteroids.

The metal oxides which are capable of adding onto a carbon-to-carbon double bond are particularly those of the higher valence stages of the heavy metals of groups 5 to 8 of the periodic system; for example osmium tetroxide, further also tungsten trioxide. The preferred peroxide compound is hydrogen peroxide. Other suitable peroxide compounds are the organic peroxides such as alkyl peroxides or per-acids, such as monoperformic acid, monoperacetic acid, monoperpropionic acid, monoperbutyric acid, monoperbenzoic acid-or monoperphthalic acid. The reaction is advantageously carried out in an anhydrous or aqueous diluent. Particularly suitable as diluents are the tertiary carbinols, such for instance as tert. butanol, and also ethers, lower fattv acid esters and chlorinated hydrocarbons, such as methylene chloride and carbon tetrachloride.

The products of manufacture may be used as medicaments or as'intermediates. Some of them are new. Thus, A -3,20-diketo-17a-hydroxy-21- halogen-pregnenes, for example A -3,ll,20-triketo-17a-hydroxy-21-bromo-pregnene or A -3,20- diketo-17a-hydroxy-21-bromo-pregnene, are new compounds which are of great importance as intermediates in the manufacture of therapeutically active substances.

The invention is set forth in greater detail in the following illustrative examples. In the latter, the relationship between parts by weight and centages are by weight.

Example 1 7.15 partsby weight of A -3-keto-21-acetoxypregnadiene are dissolved in 300 parts by volume of ether, then 29.5 parts by volume of a 1.7-rnolar ethereal solution of hydrogen peroxide are added, and a solution of 0.51 part by weight of osmium tetroxide in 100 parts by volume of ether is slowly added dr-opwise with stirring. I

After a reaction period of 48 hours, the reaction mixture is diluted with ether, the solution shaken out several times with water in order to remove excess hydrogen peroxide, then dried. with sodium sulfate, filtered and evaporated.

The residue is dissolved in 250 parts by volume of methanol, a solution of 3 parts by weight of sodium sulfite in 50 parts by volume of water is added, and the mixture is boiled for 1 hour under reflux. The reaction product is then extracted from the cooled mixture with a large quantity of ether, and the ethereal solution then washed several times with water, dried with sodium 8 .11- fate, filtered and the solvent distilled oh.

In order to re-acetylate the crude product, which is partially saponified in 21-position, the residue is dissolved in 50' parts by volume of anhydrous pyridine and then admixed with 30 parts by volume of acetic anhydride. After standing for 16 hours at -25", the solution is evaporated to complete dryness under vacuum at a bath temperature of 35-40% From the reaction product, by crystallization from ether, there is obtained crude A -3,20-diketo-17a-hydroxy-21-acetoxy-pregnene which, after a single recrystallization from acetone-ether, melts at 236-238 (with decomposition), [a]- =-.-.+120:e (c=0.539 in acetone).

A further quantity of pure A -3',2,0-diket017alhvdroxy-Zl-acetoxy-pregnene is obtained from the mother liquor by adsorption on aluminum oxide.

Example 2 3.565 parts by-weightof A -3-keto-21-acetoxypregnadiene are dissolved in 50' parts by volume of tert. butanol, and then 13.5 parts by volume of a; 1.5-molar solution of hydrogen peroxide in tert. butanol are added. While stirring constantly, 10 parts by volume of a solution of 0.255 part by weight of osmium tetroxide in 25 parts by volume of tert. butanol are added in the course of 5 minutes, the remainder being added in portions of 1 part by volume each at intervals of 2 hours each. After stirring the reaction mixture for an additional 36 hours at 25, it is diluted with 200 parts by volume of water and the oxidation product is taken up in methylene chloride. The combined methylene chloridesolutions are washed with 5% ferrous sulfate solution and Water, dried with sodium sulfate and evaporated.

The partly crystalline residue is dissolved in 125 parts by volume of methanol, then a solution of 1.5 parts by weightof 85% sodium sulfitein 25 parts by volume of Water is added, and the solution boiled for a half hour under reflux. The cooled mixture is diluted with 200 parts by volume of water, the organic substance takenup in-methylene chloride, and the combined methylen chloride solutions washed several times with water, dried with sodium sulfate and evaporated.

The residue is dissolved in 12.5 parts. by volume of anhydrous pyridine, 7.5 parts by volume of acetic anhydride are then added, and th mixture, from which crystals begin to separate in a few minutes, is allowed to stand for 16 hours at 20". The readily volatile substances are then distilled 4 ofi at a bath temperature of 40-50 under a water-jet vacuum, and the residue is stirred up with 5 parts by volume of ether. Afterstanding for several hours, the brown-colored mother liquor is subjected to suction filtration, and the separated crystals are washed with a small quantity of ether. Bya single recrystallization from acetone, the A -3,20-diketo-17a-hydroxy-21-acetoxy-pregnene of the formula CHzOCOCHl is obtained in the form of colorless prisms which melt at 236*238 and have a specific rotation [a] =-+121j:4 (0:0.515 in acetone).

By carrying out the oxidation procedure described in this exampl with a A ii-keto-pregnadiene substituted in the 2l-position by propionyloxy, succinyloxy or benzoyloxy, the 21-11mpionyloxy-, 2 1-succiny1oxy or 2lbenzoyloxy- A -3,20-diketo-17a-hydroxy-pregnene, respectively. is obtained.

Example 3 3565- parts by weight of A ll-3 -keto-2leacetoxy-pregnadiene are dissolved in 150 parts by volume of anhydrous ether, and then 29.5 parts by volume of a 1.7-molar ethereal solution of hydrogen peroxide are added, this corresponding to twice the molar proportion of hydrogen peroxide; according to Example 1. While stirring constantly, 5, parts by volume of a solution of 0.255 part by weight of osmium tetroxide in 25 parts by volume of anhydrous ether are first added in the course of 5 minutes, and the-re mainder then added in portions of 1 part by volume each at intervals of 2 hours each. Upon completion of the addition, stirring is continued for a further 48 hours at room temperature.

The material is worked upafterthe manner described in Example 2. From the obtained crystalline fraction, there is recovered by a single recrystallization from acetone, pure 4 -320- diketo-17a-hydroxy-21-acetoxy pregnene, melting at 236-238 and having a specific rotation [a] =+12O-J:40 (c 0-.539 in acetone).

Example 4 3.775 parts by weight of finely pulverized A 3-keto-21-bromo-pregnadiene are dissolved in 100 parts by volume of tert. butanol, then 13.5 parts by volume of a l.5-molar solution of hydrogen peroxide in tert. butanol are added, and th n. h le. on ant st rin a l tion i 0-25 ar b ei t Qsmwm trox in art by volume oi tert. b'utanol is added within a period of 48 hours. Upon completion of the addition, stirring of the mixture is continued'at room temperature for 96 more hours. The mixture is then diluted with 1000 parts by volume of water, after which it is extracted with large quantities of ether. The ether extracts are washed successiyay with water, 5% ferrous sulfate solution and waterand then the combined ether solutions are shaken for 18 hours with a solution of 3.0, parts by weight of sodium suliite 250 parts by volume of water. The

CHzBr crystallizes out in finely granular form, upon standing. After a single recrystallization from methylene chloride or acetone, the pure bromoketol is obtained as colorless granules which melt at 187-189 with decomposition.

[a] -=+l29i4 (:1.013 in dioxane) If the oxidation is carried out with A -3-keto- 21-chloro-pregnadiene the A 3,20 diketo-17ahydroxy-2l-chloro-pregnene is formed. Analogous compounds may also be used, which carry in 11 or 12-position a substituent such as a keto group. In this manner, A 3,11,20-triketo-1'7ahydroxy-2l-bromo-pregnene may be obtained.

150 parts by volume of dry acetone are poured over 1.05 parts by weight of A -3,20-dlkBtO17ahydroxy-2l-bromo-pregnene and 9.82 parts by weight of finely pulverized anhydrous potassium acetate and the mixture boiled for 1 hour. The solvent is then evaporated in vacuo and the residue is extracted with ether, after the addition of water. 2% sodium bicarbonate solution and water, dried with sodium sulfate, and the ether distilled off. By recrystallization of the crude product from acetone, there is obtained the previously-described A -3,20-diketo 17a-hydroxy-21-acetoxypregnene which melts at 236-238".

Example 3.725 parts by weight of A -3,11-diketo-21- acetoxy-pregnene are dissolved in 150 parts by volume of 0.2-molar hydrogen peroxide in tert. butanol. To the resultant solution, there is added, within a period of 32 hours and while stirring, a solution of 0.255 part by weight of osmium tetroxide in 25 parts by volume of tert. butanol. Stirring is continued at 25-30 for an additional 48 hours, following the completion of the addition of the osmium tetroxide. After dilution with 150 parts by volume of methylene chloride, the reaction mixture is shaken with a solution of 3 parts by weight of 85% sodium sulfite in '75 parts by volume of water for 24 hours, then diluted with water, and extractedseveral times with methylene chloride. The methylene chloride solutions are washed thoroughly with water, dried with sodium sulfate and evaporated.

, In order to re-acetylate the reaction product, which is partly saponified in the 21-position, the residue is dissolved in 12.5 parts by volume of anhydrous pyridine and admixed with 7.5 parts by volume of acetic anhydride. .After standing for '16 hours, the reaction mixture is evaporated under vacuum at room temperature, then'esidue taken up in methylene chloride, and the solution washed successively with l-normal hydrochloric acid, 0.5-normal sodium bicarbonate solution and The ether extracts are washed with water. After drying with sodium sulfate, the methylene chloride is distilled off and the residue chromatographed over aluminum oxide. Part of the oxidation product is extracted with benzene and mixtures of benzene and ether. From the fractions dissolved out with pure ether and mixtures of ether and acetone, there is recovered, after recrystallization from acetone-ether, pure 3,11,20-triketo-17a-hydroxy-21-acetoxy-pregnane of the formula C1110 C O CH:

O .-OH

as colorless crystals which melt at 232-234 (with discoloration and which have a specific rotation [a] =|-87i4: (0:0.524 in acetone).

The specified process may also be carried out with A -3-keto-pregnadiene carrying an etherified hydroxy group in 21-position. Thus, as a result of the oxidation of A -3-keto-21-methoxy-pregnadiene and A -3-keto-2l-benzyloxypregnadiene, A -3,20-diketo 17a hydroxy 21 methoxy-pregnene and A -3,20-diketo-17a-hy droxy-21-benzyloxy-pregnene are obtained.

Example 6 3.145 parts by weight .of A 7-3-keto-21-hydroxy-pregnadiene are dissolved in 50 parts by volume of tert. butanol, whereupon 12.1 parts by volume of a 1.66-molar solution of hydrogen peroxide in tert. butanol are added. While stirring constantly, 10 parts by volume of a solution of 0.255 part by weight of osmium tetroxide in 25 parts by volume of tert. butanol are added in the course of 3 minutes, the remainder being added within the course of 30 hours. In order to complete the reaction, the mixture is then stirred for an additional 32 hours. It is then diluted with 250 parts by volume of methanol, admixed with a solution of 3 parts by weight of sodium sulfite in 65 parts by volume of water, and boiled 30 minutes under reflux. After cooling to 30-40, the organic solvents are distilled off undervacuum while 250 parts by volume of water are added, and the reaction mixture is taken up in methylene chloride. The methylene chloride solution is washed a number of times with water, dried with sodium sulfate, and evaporated.

The thus obtaine A -3,20dlkel 017a,21di+ hydroxy-pregnene is, as described in Example 2, acetylated and further worked up. By recrystallization from a small quantity of acetone and recrystallization from acetone-ether, there is obtained pure A3,20-diketo-17c-hydroxy-21acetoxy-pregnene which melts at 236-238 and has a specific rotation [a] :+124i4 (c=0.502 in acetone).

Example 7 0.128 part by weight of osmium tetroxide is added to a solution of 1.783 parts by weight of AS -3-l;eto-21-acetoxy-pregnadiene in. 60 parts by volume of ether. While stirring, 46 parts by volume of a 0.217-mo1ar solution of monoperphthalic acid in ether are allowed to flow in in the course of 6 hours. When the addition is complete, stirring is continued for 46 hours, then the reaction mixture is diluted with 100 parts by volume of methanol and shaken for 12 hours with a solution of 1.5 parts by weight of sodium sulfite of 85 per cent. strength in 100 parts by volume of water. The organic solvents are removed in vacuo, the oxidation product is taken up in 500 parts by volume of ether and the ether solutions are washed consecutively with an acidified 0.5-molar solution of potassium iodide, water, a 0.5-molar solution of sodium thiosulfate, a 0.5- molar sodium carbonate solution and water. The combined ether solutions are dried with sodium sulfate, filtered and evaporated. The residue is dissolved in 7.5 parts by volume of anhydrous pyridine and mixed with 4.5 parts by volume of acetic anhydride. After 14 hours standing with the exclusion of moisture, the whole is evaporated at under a water-jet vacuum and the acetylation product which is in part crystalline is stirred Example 8 A solution of 7.13 parts by weight of A -3 keto-Zl-acetoxy-pregnadiene in parts by volume of tertiary butanol is treated with 20.5 parts by volume of a 1.95-mo1ar solution of tertiary butyl hydroperoxide in tertiary butanol. While stirring, a solution of 0.51 part by Weight of osmium tetroxide in 25 parts by volume of tertiary butanol is added within 30 hours. Stirring is continued for another hours whereupon the reaction mixture is carefully diluted with 30 parts by volume of water. The separated crystals are washed with 75% aqueous tertiary butanol in a suction-filter apparatus. From the dried crude product, there is obtained, after a single recrystallization from acetone and decoloration by means of activated charcoal, the A -3,20diketol7nhydroxy-Zl-acetoxy-pregnene in colorless prisms of M. P. 236-238.

Example 9 A solution of 2.015 parts by weight of A 3B,21 diacetoxy-allopregnene in 100 parts by volume of tertiary butanol is mixed with 10.2 parts by volume of a 1.47-molar solution of hydrogen peroxide in tertiary butanol. While stirring, a solution of 0.128 part by weight of osmium tetroxide in 25 parts by volume of tertiary butanol is added within 5 hours. Stirring is continued for another 48 hours to complete the reaction. The reaction mixture is then diluted with 100 parts by volume of methanol and shaken for 16 hours with a solution of 1.5 parts by weight of sodium sulfite of 85 per cent. strength in 100 parts by volume of water. The organic solvents are thereupon completely distilled ofi while allowing '75 parts by volume of water to flow in and the oxidation product is taken up in ether. The ether solutions are consecutively washed with water, 2%

sodium hydrogen carbonate solution and water,

p 16 hours.

separable portions with "benzene, there is obtained by elutriation with ether and subsequent recrystallization from a mixture of benzene and methanol the 3,8,2-1-d'iacetoxy-l7a-hydroxy-20-ketoallopregnane (diacetate of Reichsteins substance P) of the formula (dHzOCOCHa Al Ff HaCCOO Example 10 15 parts by volume of a 0.135-molar solution of hydrogen peroxide in tertiary butanol are poured on 0.372 part by weight of A -3-keto lid-hydroxy-fi-acetoxy-pregnadiene. Upon occasional agitation within 8 hours, a solution of 0.026 part by weight of osmium tetroxide in 4 parts by volume of tertiary butanol is added. After a further 48 hours standing, the reaction mixture is diluted with 20 parts by volume of methanol, mixed With a solution of 0.3 part by weight of sodium sulfite of per cent. strength in 20 parts by volume of water and shaken for The organic solvents are then distilled off in vacuo at 40, the oxidation product is taken up in methylene chloride, the methylene chloride solutions are consecutively washed with water, 2% sodium hydrogen carbonate solution and water, dried with sodium sulfate and evaporated.

The residue is dissolved in 10 parts by volume of anhydrous methylene chloride, treated with 2.5 parts by volume of dry pyridine and the soluv tion cooled in ice water mixed with 1.5 parts by volume of acetic anhydride. After 16 hours standing at 0, it is shaken with ice and dilute hydrochloric acid, diluted with a further quantity of methylene chloride, thoroughly Washed with water and then with 2% sodium hydrogen carbonate solution and water, dried and evaporated. The crude acetylation product is dissolved in benzene and chromatographed over 10 parts by weight of Florida bleaching earth.

As eluating agents, mixtures of benzene and ether, ether and chloroform, and chloroform and methanol are used. The fractions, melting between 205 and 218 and capable of considerably reducing silver diamine solution, are united and again purified by adsorption on Florida bleachin ear The o dation pr du t whi h thu freed from slightly reducing accompanying sub? stances is recrystallized from a'mixture of ethyl acetate and ether and from acetone whereby the A 3,20 diketo 115.1% dihy'droxy 21- acetoxy-pregnene (acetate of Reichsteins substance M) of the formula onto 0 CH1,

is obtained in colorless prisms of M. P. 220-222 and of specific rotation [a] =+148i4 (c=0.434 in acetone).

What is claimed is:

1. A process for the preparation of a 17,20- hydroxy-ketone of the pregnane series, which comprises subjecting a pregnene having the grouping =CH-CH2X in the 17-position, X representing a member selected from the group consisting of free, esterified and etherified hydroxyl, with osmium tetraoxide and with a member selected from the group consisting of hydrogen peroxide, an alkyl peroxide and a peracid, and isolating the resultant 17,20-hydroxxy-ketone from the reaction mixture.

2. A process for the preparation of a 17,20- hydroxy-ketone of the pregnane series, which comprises subjecting a A -3-keto-pregnene having the grouping :CI-I-CI-IzX in the 17-position, X representing a member selected from the group consisting of free, esterified and etherified hydroxyl, with osmium tetroxide and with a member selected from the group consisting of hydrogen peroxide, an alkyl peroxide and a peracid, and isolating the resultant 17,20-hydroxy-ketone from the reaction mixture.

3. A process for the preparation of a 17,20- hydroxy-ketone of the pregnane series, which comprises subjecting a 3-acy1oxy-pregnene having the grouping =CH-CH2X in the 17- position, X representing a member selected from the group consisting of free, esterified and etherified hydroxyl, with osmium tetroxide and with a member selected from the group consisting of hydrogen peroxide, an. alkyl peroxide and a peracid, and isolating the resultant 17,20-hydroxyketone from the reaction mixture.

4. A process for the preparation of a 17,20-

10 hydroxy-ketone of the pregnane series, which comprises subjecting a 3,11-diketo-pregnene having the grouping =CH-CH2X in the 17-position, X representing a member selected from the group consisting of free, esterified and etherified hydroxyl, with osmium tetroxide and with a member selected from the group consisting of hydrogen peroxide, an alkyl peroxide and a peracid, and isolating the resultant 17,20-hydroxy-ketone from the reaction mixture.

5. A process for the preparation of a 17,20- hydroxy-ketone of the pregnane series, which comprises subjecting a A 3-keto-2l-acetoxypregnadiene with osmium tetroxide and with a member selected from the group consisting of hydrogen peroxide, an alkyl peroxide and a peracid, and isolating the resultant 17,20-hydroxyketone from the reaction mixture.

6. A process for the preparation of a 17,20- hydroxy-ketone of the pregnene series, which comprises subjecting a pregnene having the rouping =CH--CH2X in the 17-position, X representing a member selected from the group consisting of free, esterified and etherified hydroxyl, with osmium tetroxide and hydrogen peroxide, and isolating the resultant 17,20-hydroxy-ketone from the reaction mixture.

7. The Ar -3,20 diketo 17a hydroxy 21- halogen-pregnenes.

8. Th A -3,20-diketo-17a-hydroxy-2l-bromopregnene, melting at about 187189 with decomposition.

KARL MIESCHER. JULIUS SCHMIDLIN.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,228,706 Reichstein Jan. 14, 1941 2,275,790 Miescher Mar. 10, 1942 2,437,564 Serini Mar. 9, 1948 2,492,194 Sarett Dec. 27, 1949 2,596,563 Kaufmann May 13, 1952 OTHER REFERENCES Salmon, Helv. Chem. Acta. 30, 1616-1635 (1947). 

1. A PROCESS FOR THE PREPARATION OF A 17,20HYDROXY-KETONE OF THE PREGNANE SERIES, WHICH COMPRISES SUBJECTING A PREGNENE HAVING THE GROUPING =CH-CH2X IN THE 17-POSITION, X REPRESENTING A MEMBER SELECTED FROM THE GROUP CONSISTING OF FREE, ESTERIFIED AND ETHERIFIED HYDROXYL, WITH OSMIUM TETRAOXIDE AND WITH A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROGEN PEROXIDE, AND ALKYL PEROXIDE AND A PERACID, AND ISOLATING THE RESULTANT 17,20-HYDROXXY-KETONE FROM THE REACTION MIXTURE. 